The present invention relates generally to the chemical preparation of isocoumarin compounds. More specifically, the invention relates to the conversion of homophthalic anhydrides to isocoumarins and the preparation of homophthalic acid intermediates. Isocoumarin derivatives are valuable compounds in the fields of angiogenesis inhibition, immuno-regulation, and cancer therapy.
Isocoumarins have been synthesized by a number of different methods. These methodologies include, but are not limited to: oxidation of indenes, indanone and indenones; condensation via Stobbe condensation with aldehydes and ketones and Claisen condensation with formates and oxalates; cyclization of 2-carboxybenzyl ketones, 2-vinylbenzoic acids, xcex1-cyanohomophthalic acids and 2-formylbenzoates; and reduction of phthalides. For reviews of isocoumarin synthesis, see Barry, Chemical Rev. 64:229-260, 1964; Napolitano, Org. Prep. Proced. Int. 29:631-664, 1997.
Homophthalic anhydrides have also been utilized in the synthesis of isocoumarin derivatives. 2-Carboxyphenylacetates can be prepared by methanolysis of homophthalic anhydrides. Lithium borohydride reduction of these half-esters yields 3,4-dihydroisocoumarins. (Bose and Chaudhury, Tetrahedron. 20:49-51, 1964). Condensation of homophthalic anhydride with hydroquinone in the presence of stanic chloride yields 2-(2,5-dihydroxyphenyl) isocoumarin (Sorrie and Thomson, J. Chem. Soc. 2244, 1955). Homophthalic anhydride adds to ferrocene to produce ferrocenylhomophthalic acid, which can be cyclized to 3-ferrocenylisocoumarin (Boichard, Compt. Rend. 253:2702, 1961). Further, Perkin condensation of homophthalic anhydrides with aromatic aldehydes in the presence of bases such as triphenylmethylsodium, yields 3-phenyl-3,4-dihydroisocoumarin-4-carboxylic acids (Jones and Pinder, J. Chem. Soc., 2612, 1958).
Methods for preparing isocoumarin-3-yl acetic acid derivatives are disclosed in WO0107429. In one process, a homophthalate monoester derivative is reacted with a malonic acid monoester salt in a suitable solvent in the presence of a condensing agent to form a xcex2-oxocarboxylic acid derivative, which is subsequently cyclized in a suitable inert solvent, in the presence of a base. The reaction is as follows: 
An alternative method of preparation of the same compound disclosed the reaction of a homophthalic acid derivative with a malonyl halide monoester in the presence of a base. One disadvantage of these methods is that the synthesis disclosed in WO0107429 for homophthalate esters has a low yield and provides an intermediate ester with free hydroxy groups that must be subsequently protected in a separate step.
The synthesis of 3-yl-isocoumarins is also disclosed by Tirodkar and Usgaonkar, J. Indian Chem Soc., 46, 1934-933, 1969; Tirodkar and Usgaonkar, Indian J. Chem, 9: 123-125, 1970; Tirodkar and Usgaonkar, J. Indian Chem Soc., 48:192-198, 1971; and Sinha et al, Indian J. Heterocyclic Chem., 1:235-240, 1992. These methods describe the formation of 4-carboxy-3-yl-isocoumarins by reaction of an anhydride with an isochroman-1,3-dione carbanion or enolate intermediate, formed from the corresponding homophthalate under basic conditions. Decarboxylation under acidic conditions or by heating resulted in the corresponding 3-yl-isocoumarin. This reaction is summarized in FIG. 1.
Despite the preparative methods for isocoumarins known in the art, there is still a need for economically preferable, effective and efficient process for the preparation of isocoumarin derivatives. The object of the present invention is to provide such a process. Further objects are to minimize the number of process reaction steps, to enhance overall yields of desired end products and to provide a process that is readily scalable for the production of commercial-scale quantities. Other objects and advantages will become apparent to persons skilled in the art and familiar with the background references from a careful reading of this specification.
In its most general terms, the present invention provides for the preparation of isocoumarin derivatives and intermediates useful in such preparative procedures. One aspect of the invention provides a process for preparing isocoumarin derivatives comprising reacting a homophthalic anhydride derivative with a carbonyl compound, wherein the carbonyl group is substituted with an acyl activating group, in the presence of a reaction medium comprising an inert solvent and a base. The inventors discovered this novel reaction results in the formation of isocoumarin derivatives in high yield and provides an efficient method of preparation of such compounds. Another aspect of the present invention is the preparation of homophthalate esters based on the discovery that, surprisingly, the addition of a malonate anion to a benzyne intermediate formed from a 2,4-disubtituted halobenzene, results in the selective production of a 3,5-disubstituted homophthalate ester. Such esters can be readily converted into the equivalent anhydride and are, thereby, useful in the preparation of isocoumarin derivatives according to the methods provided by the present invention
In one aspect, the present invention provides a process for the preparation of the isocoumarin derivatives of formula (1): 
where R1 and R2 independently represent hydrogen, halogen, which may be chloro, bromo, iodo of fluoro, an aryl group, a heteroaryl group, or a C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 acyl, or C1-C6 alkoxy group. R1 and R2 further independently represent the substituted amino function xe2x80x94NR4R5, where either R4 is hydrogen and R5 is sulfonyl or C1-C6 acyl or where R4 and R5 are independently C1-C6 alkyl or C1-C6 acyl. In a preferred embodiment, R1 is hydrogen. In another preferred embodiment, R2 is methyl.
R3 represents an electron withdrawing group. In preferred embodiments, R3 is an electron withdrawing group selected from aryl, hetroaryl, sulfonate, phosphonate, cyano, xe2x80x94CO2R7, wherein R7 is C1-C6 alkyl, or an acid halide xe2x80x94COR8, wherein R8 is a halogen, which may be chloro, bromo, iodo of fluoro. In a more preferred embodiment, R3 is xe2x80x94CO2C2H5. R3 may also form a ring structure with R2, wherein the ring structure incorporates an electron withdrawing element, such ring structures include anhydrides, lactones, oxo-cycloalkanes and cyclic amides, including lactams and lactims.
The substituents represented by X include halo, which may be fluoro, chloro, bromo or iodo, aryl, heteroaryl, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 acyl, or C1-C6 alkoxyl, or xe2x80x94NR4R5, where R4 and R5 are as defined above. X further represents xe2x80x94SO2R6, where R6 is C1-C6 alkyl or C1-C6 acyl. The subscript n is an integer from 0 to 4, with the caveat that when n is 2, 3 or 4, the X substituents may be the same or different. In a preferred embodiment, subscript n is 2 and X is the same and is xe2x80x94OCH3. In a more preferred embodiment, the isocoumarin derivative is 2-(6,8-dimethoxy-1-oxo-1H-isochromen-3-yl)-propionic acid ethyl ester (2) 
The process comprises reacting a homophthalic anhydride of formula (3): 
where R1, X and subscript n are as defined above, with a carbonyl compound of formula (4): 
where R2 and R3 are as defined above, and Y is an acyl activating substituent. In preferred embodiments, Y is a halogen, pyridyl or aryloxy, and more preferably imidazoyl or chloro.
The reaction medium further comprises an inert solvent and a base. In certain embodiments, the solvent is an aprotic solvent such as a halogenated or ethereal solvent. In a preferred embodiment, the solvent is acetonitrile or N-methyl pyrrolidinone. In some embodiments of the present invention, the base can be a tertiary amine, amidine, amide or a tertiary alkoxide base. In preferred embodiments, the base is triethylamine, N,N-tetramethylguanidine or 1,8-diazabicyclo[5.4.0]-undec-7-ene.
In some embodiments of the present invention, 2-(6,8-dimethoxy-1-oxo-1H-isochromen-3-yl)-propionic acid ethyl ester (2), undergoes hydrolysis to remove the ethyl ester group and the methyl group at position 8 to produce 2-(8-hydroxy-6-methoxy-1-oxo-1H-isochromen-3-yl)-propionic acid (5), also known as NM-3, which is disclosed and claimed in U.S. Pat. No. 6,020,363, hereby incorporated by reference: 
An alternative reaction to that with the carbonyl compound (4), is wherein the homophthalic anhydride (3) undergoes a self condensation to produce the isocoumarin derivatives depicted by compound (6): 
wherein R1, X and n are as previously defined. The reaction is believed to proceed in a similar fashion to that of the compounds of formula (3) with the activated carbonyl compounds of formula (4). Thus, similar reactions conditions may be used to from the condensation products of formula (6).
Another aspect of the present invention is a process for the preparation of homophthalate derivatives of formula (7): 
wherein W represents a carboxy protecting group, which in preferred embodiments is methyl or ethyl. R9 and R10 independently represent the substituents as described above for X. In preferred embodiments, R9 and R10 are independently C1-C6 alkyl or C1-C6 alkoxy. R1 is as defined above, and in a preferred embodiment is hydrogen.
The process comprises reacting a 2,4-disubstituted or a 3,5-disubstituted halobenzene derivative of formula (8) or (9) respectively: 
where R9 and R10 are as defined above, and R13 is a halogen, which, in some embodiments, is chloro, fluoro or bromo, a sulfonate ester or a leaving group such as tosylate or triflate; and a malonate ester of formula (10): 
where W and R1 are as defined above, and where in a preferred embodiment, R1 is hydrogen, in the presence of a solvent and a strong base, for example a base with a pKa in water of about 30 or above. In a preferred embodiment, the solvent is tetrahydrofuran. In other preferred embodiments, the strong base is lithium diisopropylamide (LDA), lithium tetramethylpiperidide, lithium hydride or a mixture of bases such as LDA and sodium hydride or potassium hydride. In other preferred embodiments, R13 is chloro or bromo.
In some embodiments, the malonate ester (10) is first reacted with a strong base to form a malonate ester salt (11): 
wherein M+ is a monovalent cation. The base may be alkali metal base, which may be sodium hydride or lithium hydride, wherein M+ in the malonate salt (11) is Na+ and Li+ respectively. Either the 2,4-disubstituted halobenzene (8) or 3,5-disubstituted halobenzene (9) is then added with the optional addition of a second strong base, the addition of which can be either before or after the addition of the disubtituted halobenzene. In a preferred embodiment, the optional second strong base is added after the disubtituted halobenzene (8) or (9). In another preferred embodiment, the optional second strong base is LDA.
The process according to the present invention is highly selective in that the desired homophthalate derivative of formula (7) is produced in a molar ratio of at least about 7.0:3.0, or in a molar ratio of at least about 8.0:2.0, or in a molar ratio of at least about 9.0:1.0 in comparison to the homophthalate derivative of formula (12). In a preferred embodiment, the desired homophthalate (7) is produced substantially free of the positional isomer (12), that is, in a molar ratio of at least about 9.5:0.5 of (7):(12). In another preferred embodiment, there is no detectable level of the homophthalate derivative of formula (12) produced during the reaction of a disubstituted halobenzene derivative of formula (8) or formula (9) and a malonate ester of formula (10), as measured by HPLC and U.V. analyses. 
The process further comprises embodiments wherein the carboxy protecting groups W are removed to form the homophthalic acid derivative of formula (13): 
In some embodiments, the homophthalic acids of formula (13) undergo dehydration to form the homophthalic anhydrides of formula (14): 
wherein R1, R9 and R10 are as defined above.
The process of the invention also further comprises reacting the anhydride of formula (14) with a carbonyl compound of formula (4), wherein the reaction medium comprises a solvent and a base to afford the derivatized isocoumarin product. In some embodiments, the carbonyl compound of formula (4) is the carbonyl compound of formula (15): 
wherein R11 and R12 are independently C1-C6 alkyl, and Y is an acyl activating group. In a preferred embodiment, the reaction of the anhydride of formula (14) wherein R1 is hydrogen, with the carbonyl compound of formula (15) results in the formation of the isocoumarin derivative of formula (16): 
In a preferred embodiment, where R9 and R10 are methoxy, R11 is methyl and R12 is ethyl, the reaction process of the present invention provides the isocoumarin derivative 2-(6,8-dimethoxy-1-oxo-1H-isochromen-3-yl)-propionic acid ethyl ester (2). In another preferred embodiment, the process further comprises removal of the ethyl ester group and the methyl group at position 8 of 2-(6,8-dimethoxy-1-oxo-1H-isochromen-3-yl)-propionic acid ethyl ester (2) to provide 2-(8-hydroxy-6-methoxy-1-oxo-1H-isochromen-3-yl)-propionic acid (5).
Also within the scope of the invention is an integrated stepwise process wherein isocoumarins of formula (1) are prepared starting from a substituted halo-benzene of formula (8) or formula (9) which is reacted with a malonate ester of formula (10) to afford a homophthalate derivative of formula (7), which in turn, after optional deprotection/dehydrations, is reacted with a carbonyl compound of formula (4) to afford the desired isocoumarin derivatives.